Ifosfamide (IFO), which is used in the treatment of pediatric solid tumors, causes high rates of nephrotoxicity. N‐acetylcysteine (NAC), an antidote for acetaminophen overdose, has been shown to prevent IFO‐induced renal cell death and nephrotoxicity in both LLCPK‐1 cells and a rat model. To facilitate the use of NAC in preventing IFO‐induced nephrotoxicity in children, the authors compared the systemic exposure to NAC in children treated for acetaminophen overdose to the systemic exposure of the therapeutically effective rat model. The mean systemic exposure in the rat model was 18.72 mM·h (range, 9.92–30.02 mM·h), compared to the mean systemic exposure found in treated children (14.48 mM·h; range, 6.22–32.96 mM·h). They also report 2 pediatric cases in which NAC‐attenuated acute renal failure associated with IFO when given concurrently with their chemotherapy treatment. Systemic exposure to NAC measured in 1 of these cases was comparable to that in the children treated for acetaminophen overdose. These results corroborate NAC's potential to protect against IFO‐induced nephrotoxicity in children when used in its clinically approved dose schedule and supports a clinical trial in children.

Ifosfamide-induced nephrotoxicity is a serious adverse effect in children undergoing chemotherapy. Our previous cell and rodent models have shown that the antioxidant N-acetylcysteine (NAC), used extensively as an antidote for acetaminophen poisoning, protects renal tubular cells from ifosfamide-induced nephrotoxicity at a clinically relevant concentration. For the use of NAC to be clinically relevant in preventing ifosfamide nephrotoxicity, we must ensure there is no effect of NAC on the antitumor activity of ifosfamide. Common pediatric tumors that are sensitive to ifosfamide, human neuroblastoma SK-N-BE(2) and rhabdomyosarcoma RD114-B cells, received either no pretreatment or pretreatment with 400 µmol/L of NAC, followed by concurrent treatment with NAC and either ifosfamide or the active agent ifosfamide mustard. Ifosfamide mustard significantly decreased the growth of both cancer cell lines in a dose-dependent manner (p < 0.001). The different combined treatments of NAC alone, sodium 2-mercaptoethanesulfonate alone, or NAC plus sodium 2-mercaptoethanesulfonate did not significantly interfere with the tumor cytotoxic effect of ifosfamide mustard. These observations suggest that NAC may improve the risk/benefit ratio of ifosfamide by decreasing ifosfamide-induced nephrotoxicity without interfering with its antitumor effect in cancer cells clinically treated with ifosfamide.

The antineoplastic drug ifosfamide (IFO) in the treatment of solid tumors, particularly in children, is the cause of severe nephrotoxicity. Although it is a potent and effective chemotherapeutic agent, the associated nephrotoxicity has a serious impact on the health and the quality of life of exposed children. The toxic metabolite of IFO thought to be responsible for IFO-induced kidney damage is chloroacetaldehyde (CAA). Those suffering from nephrotoxicity typically develop tubular and glomerular toxicities, with the most severe form being Fanconi's syndrome. As the mode of toxicity of CAA seems to be primarily owing to oxidative stress, the use of antioxidants as a protective measure for the kidneys is a promising strategy. In this review, we highlight recent research that supports the local renal production of CAA as the proximate cause of IFO-induced nephrotoxicity with age as an important risk factor, those under the age of three being the most vulnerable. Most importantly, we focus on the potential advantages of the antioxidant N-acetylcysteine owing to both its antioxidant properties and its current use clinically in pediatrics.

The antineoplastic drug ifosfamide (IFO) in the treatment of solid tumors, particularly in children, is the cause of severe nephrotoxicity. Although it is a potent and effective chemotherapeutic agent, the associated nephrotoxicity has a serious impact on the health and the quality of life of exposed children. The toxic metabolite of IFO thought to be responsible for IFO-induced kidney damage is chloroacetaldehyde (CAA). Those suffering from nephrotoxicity typically develop tubular and glomerular toxicities, with the most severe form being Fanconi's syndrome. As the mode of toxicity of CAA seems to be primarily owing to oxidative stress, the use of antioxidants as a protective measure for the kidneys is a promising strategy. In this review, we highlight recent research that supports the local renal production of CAA as the proximate cause of IFO-induced nephrotoxicity with age as an important risk factor, those under the age of three being the most vulnerable. Most importantly, we focus on the potential advantages of the antioxidant N-acetylcysteine owing to both its antioxidant properties and its current use clinically in pediatrics.

This study presents a meta-analysis of the influence of several potentially biasing factors (eg industry support, extrapyramidal side effects) on efficacy of studies comparing second-generation antipsychotic (SGA) with first-generation antipsychotic (FGA) medications. We used the dataset from our previously published meta-analysis of 124 randomized controlled trials (RCTs) comparing SGAs with FGAs, to evaluate whether certain possible biases could influence the actual outcome on the total score of the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impressions (CGI) scores. Industry sponsorship was determined by contact with authors or publication statement. We calculated whether (1) industry sponsorship, (2) study quality, (3) extrapyramidal symptoms (EPS) properties, or (4) prophylactic antiparkinsonian medications influenced SGA vs FGA efficacy for each drug and averaged overall by two Hedges and Olkin-based meta-analyses. The analysis found that none of the factors was significantly associated with a particular outcome. While industry-sponsored articles may conclude their medication to be more favorable than that of a competitor in an RCT, we found that the observed efficacy was not influenced by sponsorship. Many attribute the finding that SGAs appears to be more efficacious than FGAs to be a result of EPS-decreasing efficacy (or its measurement). We were unable to confirm that the drug's EPS properties or antiparkinsonian management altered actual efficacy.

Increased fat deposition in skeletal muscle is associated with insulin resistance. However, exercise increases both intramyocellular fat stores and insulin sensitivity, a phenomenon referred to as "the athlete's paradox". In this study, we provide evidence that augmenting triglyceride synthesis in skeletal muscle is intrinsically connected with increased insulin sensitivity. Exercise increased diacylglycerol (DAG) acyltransferase (DGAT) activity in skeletal muscle. Channeling fatty acid substrates into TG resulted in decreased DAG and ceramide levels. Transgenic overexpression of DGAT1 in mouse skeletal muscle replicated these findings and protected mice against high-fat diet-induced insulin resistance. Moreover, in isolated muscle, DGAT1 deficiency exacerbated insulin resistance caused by fatty acids, whereas DGAT1 overexpression mitigated the detrimental effect of fatty acids. The heightened insulin sensitivity in the transgenic mice was associated with attenuated fat-induced activation of DAG-responsive PKCs and the stress mediator JNK1. Consistent with these changes, serine phosphorylation of insulin receptor substrate 1 was reduced, and Akt activation and glucose 4 membrane translocation were increased. In conclusion, upregulation of DGAT1 in skeletal muscle is sufficient to recreate the athlete's paradox and illustrates a mechanism of exercise-induced enhancement of muscle insulin sensitivity. Thus, increasing muscle DGAT activity may offer a new approach to prevent and treat insulin resistance and type 2 diabetes mellitus.

Background Ifosfamide, which is routinely given to treat a variety of solid tumours in children, causes serious nephrotoxicity in treated children. Previous in vitro studies have shown that depletion of intracellular glutathione can enhance ifosfamide nephrotoxicity. Presently, there is no therapeutic agent that can prevent ifosfamide nephrotoxicity. We have recently shown that N-acetylcysteine (NAC) at 0.4mM prevents ifosfamide-induced nephrotoxicity in vitro. However, this in vitro concentration of NAC needed to be compared to those used in human pharmacokinetic studies since the in vitro pharmacological effect of a compound is achieved at concentrations exceeding those used in clinical. Objective The aim of the present study was to verify whether the in vitro concentration of NAC, which was found to protect renal cells from ifosfamide-induced damages, is comparable to the currently used clinical concentrations. Methods A systematic literature review of all published papers reporting on the pharmacokinetics of NAC in humans was conducted. Results The steady state concentrations of NAC administered intravenously to humans ranged from 0.04mM to 0.9mM and the urine concentration of NAC was 2mM. Conclusion This suggests that the concentration chosen for in vitro studies is well within the range of clinical levels.

BackgroundIfosfamide, which is routinely given to treat a variety of solid tumours in children, causes serious nephrotoxicity in treated children. Previous in vitro studies have shown that depletion of intracellular glutathione can enhance ifosfamide nephrotoxicity. Presently, there is no therapeutic agent that can prevent ifosfamide nephrotoxicity. We have recently shown that N-acetylcysteine (NAC) at 0.4mM prevents ifosfamide- induced nephrotoxicity in vitro. However, this in vitro concentration of NAC needed to be compared to those used in human pharmacokinetic studies since the in vitro pharmacological effect of a compound is achieved at concentrations exceeding those used in clinical.ObjectiveThe aim of the present study was to verify whether the in vitro concentration of NAC, which was found to protect renal cells from ifosfamide-induced damages, is comparable to the currently used clinical concentrations.MethodsA systematic literature review of all published papers reporting on the pharmacokinetics of NAC in humans was conducted.ResultsThe steady state concentrations of NAC administered intravenously to humans ranged from 0.04mM to 0.9mM and the urine concentration of NAC was 2mM.ConclusionThis suggests that the concentration chosen for in vitro studies is well within the range of clinical levels.

Ifosfamide (IF) nephrotoxicity is a serious adverse effect in children undergoing chemotherapy. Previous studies have shown that, in addition to the renal production of chloroacetaldehyde, a toxic metabolite of IF, lower levels of glutathione (GSH) may predispose the kidney to damage. The antioxidant N-acetylcysteine (NAC) is used extensively as an antidote for acetaminophen poisoning in children by replenishing GSH levels. As it has been safely and effectively used clinically, the objective of this study was to test whether the reversal of ifosfamide-induced nephrotoxicity can be achieved by administering NAC. Supplementation with NAC may reduce or prevent the degree of cellular cytotoxicity induced by IF. Porcine renal proximal tubular (LLCPK-1) cells were treated with NAC (0.4 mM or 2.5 mM) concurrently with 1 mM IF and 50 microM L-buthionine sulfoximine (BSO). Cellular viability was assessed by alamarBlue assay at 96 h. Intracellular GSH and oxidized GSH (GSSG) levels were determined using a GSH/GSSG colorimetric detection kit. A significant 60% decrease in cellular viability occurred when cells were treated daily with BSO and IF for 96 h. This decrease was significantly reduced when cells were concurrently treated with NAC in a concentration-dependent manner. Intracellular and total GSH levels in cells receiving concurrent treatment of NAC were significantly higher than those without NAC treatment. NAC protects renal tubular cells from IF-induced cytotoxicity. It is likely that NAC is protecting the cells by partially acting as a precursor for GSH synthesis. This mode of therapy may allow for protecting children from life-threatening nephrotoxicity induced by IF.

Obesity is associated with increased macrophage infiltration and production of proinflammatory cytokines in adipose tissue. Most resident macrophages in adipose tissue are derived from circulating blood monocytes. It has been hypothesized that hypertrophic and/or degenerating adipocytes are the signaling source for initial monocyte extravasations by increasing the production and secretion, directly or indirectly, of monocyte chemoattractant protein-1 (MCP-1) in obese adipose tissue. In the present study, we examined several factors that are potentially related to the upregulation of MCP-1 expression in adipocytes. 1) Wefound that Intralipid and palmitate are potent stimuli of MCP-1 expression in adipocytes and preadipocytes, and that the effects of lipids and TNF-α on MCP-1 expression are additive. 2) We found no increased MCP-1 expression in aged adipocytes during prolonged tissue culture of 3T3-L1 adipocytes. 3) We ruled out the presence of a positive correlation between adipocyte MCP-1 mRNA expression and adipocyte cell size in both cultured adipocytes and in size-fractionated primary adipocytes isolated from diet-induced and genetic obese mouse models. Taken together, these results indicate that hypertrophic or degenerating adipocytes are not intrinsically linked to higher MCP-1 expression, but may induce MCP-1 over-expression in adipocytes and other stromal cells in the obese state by releasing into extracellular milieu more free fatty acids because of exaggerated lipolysis. Copyright © 2006 by New Century Health Publishers, LLC.

ResumenEn nuestra opinión, la mejor guía para prescribir antipsicóticos es la experiencia del profesional clínico con sus pacientes y en particular, el paciente al que se está tratando. Si el tratamiento funciona, aférrate a el. Pensamos que es importante también que el profesional clínico considere los datos de los estudios doble ciego de asignación aleatoria bien controlados porque, en la “medicina basada en los datos”, los sesgos tanto conocidos como desconocidos se controlan por el diseño ciego y la distribución al azar. El próposito de este artículo es resumir y analizar los datos sobre eficacia. La elección de antipsicótico, en nuestra opinión, es probablemente la decisión más importante que el profesional clínico toma a favor del paciente psicótico. Esto implica la elección del medicamento, sus dosis y equilibrar la eficacia, los efectos secundarios y el coste.

Insulin resistance is often associated with obesity. We tested whether augmentation of triglyceride synthesis in adipose tissue by transgenic overexpression of the diacylglycerol aclytransferase-1 (Dgat1) gene causes obesity and/or alters insulin sensitivity. Male FVB mice expressing the aP2-Dgat1 had threefold more Dgat1 mRNA and twofold greater DGAT activity levels in adipose tissue. After 30 weeks of age, these mice had hyperglycemia, hyperinsulinemia, and glucose intolerance on a high-fat diet but were not more obese than wild-type littermates. Compared with control littermates, Dgat1 transgenic mice were both insulin and leptin resistant and had markedly elevated plasma free fatty acid levels. Adipocytes from Dgat1 transgenic mice displayed increased basal and isoproterenol-stimulated lipolysis rates and decreased gene expression for fatty acid uptake. Muscle triglyceride content was unaffected, but liver mass and triglyceride content were increased by 20 and 300%, respectively. Hepatic insulin signaling was suppressed, as evidenced by decreased phosphorylation of insulin receptor-beta (Tyr(1,131)/Tyr(1,146)) and protein kinase B (Ser473). Gene expression data suggest that the gluconeogenic enzymes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, were upregulated. Thus, adipose overexpression of Dgat1 gene in FVB mice leads to diet-inducible insulin resistance, which is secondary to redistribution of fat from adipose tissue to the liver in the absence of obesity.

Renal clearance is an important route of drug elimination. While during the neonatal period there is minimal glomerular filtration and active tubular secretion of drugs, there is a well-described rapid development in these processes in the post-neonatal period. A less appreciated fact is that during toddlerhood, there is an “overshoot” of the glomerular filtration rate (GFR) well above the levels encountered in older children and adults, and there is an early achievement of adult levels in active drug secretion, which stays at a plateau throughout childhood and adulthood with an “overshoot” in toddlers due to specific transport mechanisms. This phenomenon leads to dose requirements for renally excreted drugs in this age group being, on a per-kilogram basis, much larger than in adults. This review discusses the mechanisms related to renal ontogeny in drug handling.

Unmedicated schizophrenia patients relapse at a rate of approximately 10% per month. Maintenance treatment with antipsychotic medications can reduce this rate dramatically. Ensuring compliance with medication in the maintenance treatment of schizophrenia encompasses 3 areas of concern: (1) choice of antipsychotic medication, accounting for efficacy and side effects; (2) route of administration of medications, considering the benefits and detriments of long-acting injectable and oral medications; and (3) reducing "doctor noncompliance," the failure of some physicians to perceive the need for long-term treatment for patients with chronic schizophrenia. This article focuses on the selection of the antipsychotic medication that will most likely lead to successful maintenance treatment of schizophrenia. Data from acute trials must be relied upon to evaluate the comparative risks and benefits of these agents as long-term treatments since few double-blind, random-assignment studies have compared the newer-generation antipsychotics for maintenance treatment of schizophrenia. Studies of acute treatment, as well as a small number of studies of maintenance treatment, have shown the newer-generation antipsychotics risperidone and olanzapine to be more efficacious and to have a more favorable side effect profile than conventional-generation antipsychotics. Research on the newer-generation antipsychotics, including ziprasidone, aripiprazole, and quetiapine, shows these agents to be efficacious and safe, although the limited amount of data on these agents precludes a definitive evaluation of their efficacy and safety.

Objectives: The aim of this study was to compare the effects of an infant formula fortified with nucleotides (NF) with those of a control formula (CF) on the incidence of diarrhea, respiratory tract infections (RTIs), and immune responses in healthy term infants.Methods: This 12-month, double-blind study was conducted on 1- to 7-day-old infants randomized to receive NF or CF exclusively until 12 weeks of age, and fed the assigned formula with solid food until 12 months. NF was supplemented with 72 mg/L of nucleotides, based on the total potentially available nucleotide content of human milk. Subjects were evaluated within 1 week of birth, at 4 weeks, and every 4 weeks thereafter until 48 weeks of age. The primary outcome variable was the incidence of diarrhea. Secondary variables included RTIs, serum immunoglobulin concentrations, and response to hepatitis B vaccine.Results: Compared with subjects fed CF (n = 170), those fed NF (n = 166) had a trend toward reduced risk of diarrhea from 8 to 48 weeks of age and a significantly lower risk of 25.4% (P = 0.05) between 8 and 28 weeks. NF subjects had significantly higher serum immunoglobulin A concentrations (P < 0.05) throughout the 48-week study. The NF group had an increased risk of upper RTIs, the same incidence of lower RTIs, and the same antibody response to hepatitis B vaccination as the CF group, based on one-sided tests. Growth was normal in both groups, and no adverse events were considered to be formula-related.Conclusions: Healthy term infants from 8 to 28 weeks of life are less likely to experience diarrhea and have higher serum immunoglobulin A concentrations with NF compared with formula without added nucleotides.

Stimulated by Dawkins and colleagues' (1999) and Remington and Kapur's (2000) calls to develop clinical profiles of the new atypical antipsychotic drugs and by Mattes's critiques (1997, 1998), we performed two sets of analyses for risperidone. First, we reanalyzed data from the North American risperidone trial: risperidone was superior to haloperidol to an equal degree in patients with and without the deficit syndrome, in patients with paranoid and nonparanoid schizophrenia, in treatment-resistant and treatment-responsive patients (patients hospitalized for longer and shorter periods), and in patients with or without weight gain. Moreover, risperidone was more effective than haloperidol on symptoms nonresponsive and responsive to haloperidol; its effects on negative symptoms were independent of its effects on extrapyramidal symptoms; and it was effective in treating depression in schizophrenia. Second, we performed a meta-analysis of 18 controlled risperidone trials: risperidone was consistently more effective than conventional antipsychotics in treating positive and negative symptoms.

The objective of this study was to test whether the gastrointestinal tolerance of a new infant formula equalled or exceeded the tolerance of other milk-based infant formulas, and to compare the tolerance of the new formula to that of human milk. This prospective, observational, multicenter, open-label study was conducted in Taiwan. Healthy, full-term infants aged 28-98 days were enrolled on their current feeding regimen (no treatment assigned). Feeding regimens included human milk (HM), a new infant formula (NF, Similac Advance), other marketed infant formulas (OF, mainly Enfalac or S-26, HM + NF and HM + OF. Data for stool frequency, stool consistency and gastrointestinal intolerance symptoms were recorded in study diaries by parents for a period of two weeks. Gastrointestinal tolerance was evaluated in 967 infants, of whom 481 (49.7%) received NF, 312 (32.2%) received OF, 101 (10.4%) received HM + NF, 41 (4.2%) received HM + OF and 32 (3.3%) received HM. Infants fed HM only had softer and more frequent stools than those who received NF only or OF only (P < 0.001). Infants fed NF only had softer stools than those fed OF only (P < 0.001), including those fed either Enfalac or S-26 (P < 0.001). There were no significant differences between feeding groups for the incidence of general intolerance, spit-up or flatulence. All feeding regimens were well tolerated. We thereby concluded that NF is well tolerated in healthy infants and results in stool consistencies that more closely resemble those of infants fed human milk than those of infants fed other formulas.

A novel method based on liquid chromatography–mass spectrometry with electrospray ionization (LC–MS) has been developed for analysis of voriconazole in aqueous humor. The separation was achieved on a reversed-phase C18 column eluted by 70% acetonitrile–30% water–0.01% TFA. The correlation between the concentration of voriconazole to peak area was linear (r2=0.9990) between 0.04 and 60 ng, with a coefficient of variance of less than 3%. Limit of quantitation (LOQ) was estimated to be 5 ng/ml voriconazole with an injection volume of 2 μl of aqueous humor. Both intra-day and inter-day imprecision were less than 3% over the whole analytical range. Parallel analyses of voriconazole samples by LC–MS and by high-performance liquid chromatography (HPLC)–UV showed that the two methods were highly correlated (r2=0.9985). LC–MS was used to the determine voriconazole levels achieved in the aqueous humor of the rabbit eye, following topical application of 5 or 10 μg voriconazole in the form of eyedrops for 11 days b.i.d. The lower dosage produced an aqueous humor concentration of 7.29±5.84 μg/ml, while the higher dosage produced a concentration of 14.56±12.90 μg/ml.

We identified Eyes absent 4 (EYA4), a member of the vertebrate Eya family of transcriptional activators, as the causative gene of postlingual, progressive, autosomal dominant hearing loss at the DFNA10 locus. In two unrelated families from Belgium and the USA segregating for deafness at this locus, we found different mutations in EYA4, both of which create premature stop codons, Although EYA proteins interact with members of the SIX and DACH protein families in a conserved network that regulates early embryonic development, this finding shows that EYA4 is also important post-developmentally for continued function of the mature organ of Corti.